Mitochondria are found in almost all eukaryotic cells and play a role in processes such as ATP production, calcium homeostasis, lipid synthesis and apoptosis signaling. Mitochondria are organized as a network that undergoes constant events of fission and fusion, processes which are critical for their cellular function. The mitochondrial network is sensitive to changes in physiological conditions, as reflected in morphological rearrangements such as hyperfusion in response to starvation and fragmentation in response to oxidative stress.
Additionally, individual mitochondria respond to various cues by changing their intracellular positioning. Mitochondrial motility is primarily based on microtubules (MT), utilizing plus end-directed kinesin motors and the minus end-directed dynein (Pilling, A. D., et al., Mol Biol Cell, 2006. 17(4): p. 2057-68). Actin involvement in mitochondrial motility was suggested long ago, when it was shown that mitochondria enter the apical microvilli of the lower malpighian tube of Rhodnius Prolixus in an actin, but not microtubule dependent manner (Bradley, T. J. and P. Satir, J Supramol Struct, 1979. 12(2): p. 165-75).
In neurons, mitochondria move in axons bidirectionally on MTs at speeds reaching ˜1 μm/sec with several arrests between runs. Actin depolymerization increases mitochondria speed, suggesting that mitochondria interact with the actin cytoskeleton with opposing effect (Morris, R. L. and P. J. Hollenbeck, J Cell Biol, 1995. 131(5): p. 1315-26). Depolymerization of MTs reduces mitochondrial speed, which is completely halted when both MTs and actin are depolymerized indicating that actin can support mitochondrial movement.
Myosins play a role in key processes such as muscle contraction, cell division, membrane trafficking, endocytosis, tension sensing and dynamic tethers (Hartman, M. A. and J. A. Spudich, J Cell Sci, 2012. 125(Pt 7): p. 1627-32; Woolner, S. and W. M. Bement, Trends Cell Biol, 2009. 19(6): p. 245-52). There are 35 classes of myosins across all eukaryotes and specifically 12 classes in humans.
Myosin 19 was recently discovered as novel mitochondria localized myosin in vertebrates. The motor domain of human myosin 19 shares ˜35% identity with other motor domains of human myosins, whereas the tail domain has no obvious homology to other human myosins (Quintero, O. A., et al., Curr Biol, 2009. 19(23): p. 2008-13). Overexpressed myosin 19 tail localizes to mitochondria, indicating that the mitochondrial targeting signal is located within residues 824-970. Overexpression of myosin 19 almost doubled mitochondrial motility while overexpression of the dominant negative tail reduced mitochondrial run lengths, indicating that myosin 19 can modulate mitochondrial motility. Myosin 19 also affected mitochondrial shape, causing mitochondria to assume a tadpole shape with a wider leading edge (Quintero et al., 2009, ibid.).
The mode by which myosin 19 interacts with the mitochondria is unknown. There is a need for peptides capable of targeting and/or delivering compounds to mitochondria in a cell.